Nanomaterials with unique magnetic, luminescent and catalytic properties are being engineered for numerous biomedical applications, ranging from imaging, diagnostics and therapy, as reported in the following references: R. Weissleder, Molecular Imaging in Cancer. Science 2006, 312, 1168-1171; N. L. Rosi, N. L et al. Oligonucleotide-Modified Gold Nanoparticles for Intracellular Gene Regulation. Science 2006, 312, 1027-1030; M. Lewin et al, Tat peptide-derivatized Magnetic Nanoparticles Allow In vivo Tracking and Recovery of Progenitor Cells. Nat Biotechnol 2000, 18, 410-414; S. George et al., Use of a Rapid Cytotoxicity Screening Approach To Engineer a Safer Zinc Oxide Nanoparticle through Iron Doping. ACS Nano 2010, 4, 15-29; T. A. Xia et al., Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs. ACS Nano 2009, 3, 3273-3286; Y. Roiter, et al., Interaction of Nanoparticles with Lipid Memberane. Nano Lett 2008, 8, 941-944; H. Vallhov, et al., Mesoporous Silica Particles Induce Size Dependent Effects on Human Dendritic Cells. Nano Letters 2007, 7, 3576-3582. However, the greatest strength of nanomaterial, which relies primarily on the enhanced physical and chemical characteristics that matter exhibits at this scale, has the potential to be its greatest liability.
Potentially harmful interactions can occur between nanomaterials and living systems, including systems in the human body. For this reason, nanomaterials must be engineered using materials that either are non-toxic, biocompatible and biodegradable or that have minimal and in some cases beneficial properties. An inflammatory response is a parameter that is often investigated to assess the effect that nanomaterials have within an organism, as reported by A. E. Nel et al, in Understanding Biophysicochemical Interactions at the Nano-bio Interface. Nat Mater 2009, 8, 543-557.
For instance, recent studies have shown that titanium oxide nanoparticles, which are widely used in cosmetics and skin care products, can elicit an inflammatory response and the generation of reactive oxygen species, causing DNA damage, according to B. C. Schanen et al., in Exposure to Titanium Dioxide Nanomaterials Provokes Inflammation of an In vitro Human Immune Construct. ACS Nano 2009, 3, 2523-2532 and A. A. Shvedova et al., in Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity using Human Keratinocyte Cells. J Toxicol Environ Health A 2003, 66, 1909-1926.
Also, single-walled carbon nanotubes can cause lipid peroxidation, oxidative stress, mitochondrial dysfunction and changes in cell morphology upon in vitro incubation with keratinocytes and bronchial epithelial cells, as discussed by C. W. Lam et al., in Histopathological Study of Single-Walled Carbon Nanotubes in Mice 7 and 90 days after Instillation into the Lungs. Abstracts of Papers of the American Chemical Society 2003, 225, U955-U955.
Furthermore, silver nanoparticles have been found to display size-dependent toxicity when exposed to alveolar macrophages via induction of oxidative stress, as reported by C. Carlson et al., in Unique Cellular Interaction of Silver Nanoparticles: Size-dependent Generation of Reactive Oxygen Species. J Phys Chem B 2008, 112, 13608-13619 and S. M. Hussain et al., in Safety Evaluation of Silver Nanoparticles: Inhalation Model for Chronic Exposure. Toxicol Sci 2009, 108, 223-224.
Quantum dots and fullerenes can also initiate an inflammatory response and the generation of reactive oxygen species, as discussed by H. H. Chen et al., in Acute and Subacute Toxicity Study of Water-Soluble Polyalkylsulfonated C60 in Rats. Toxicologic Pathology 1998, 26, 143-151; H. H. Chen et al., in Renal Effects of Water-soluble Polyarylsulfonated C60 in Rats with an Acute Toxicity Study. Fullerene Science and Technology 1997, 5, 1387-1396 and A. Nel et al., in Toxic Potential of Materials at the Nanolevel, Science 2006, 311, 622-627.
Cerium oxide nanoparticle (nanoceria) is a unique nanomaterial, because it exhibits anti-inflammatory properties. Nanoceria has been found to scavenge reactive oxygen species (ROS), possess superoxide-dismutase-like activity, prevent cardiovascular myopathy, and provide radioprotection to normal cells from radiation as reported by the following references: J. M. Perez et al., in Synthesis of Biocompatible Dextran-coated Nanoceria with pH-dependent Antioxidant Properties. Small 2008, 4, 552-556; J. P. Chen et al., in Rare Earth Nanoparticles Prevent Retinal Degeneration Induced by Intracellular Peroxides. Nature Nanotechnology 2006, 1, 142-150; J. Niu et al., in Cardioprotective Effects of Cerium Oxide Nanoparticles in a Transgenic Murine Model of Cardiomyopathy. Cardiovasc Res 2007, 73, 549-559; R. W. Tarnuzzer et al., in Vacancy Engineered Ceria Nanostructures for Protection from Radiation-induced Cellular Damage. Nano Lett 2005, 5, 2573-2577; and C. Korsvik et al., in Vacancy Engineered Ceria oxide Nanoparticles Catalyze Superoxide Dismutase Activity, Chemical Communications 2007, 1056-1058.
The synthesis of biocompatible polymer-coated nanoceria with enhanced aqueous stability and unique pH-dependent antioxidant activity was recently reported by J. M. Perez et al. in Small 2008, 4, 552-556, supra. Particularly, it was found that nanoceria displays optimal antioxidant properties at physiological pH; whereas, it behaves as an oxidase at acidic pH, according to A. Asati et al., in Oxidase-Like Activity of Polymer-Coated Cerium Oxide Nanoparticles, Angewandte Chemie-International Edition 2009, 48, 2308-2312. Hence, this selective behavior may explain nanoceria's selective cytoprotection to normal cells, but not to cancer cells during radiation treatment or oxidative stress, as discussed by R. W. Tarnuzzer et al., in Nano Lett 2005, 5, 2573-2577, supra.
In addition, the nature of the polymeric coating surrounding the cerium oxide core could play a critical role in nanoceria's beneficial (antioxidant) vs harmful (oxidant) properties. It was hypothesized that the cytotoxicity of cerium oxide nanoparticles could depend upon their subcellular localization. Once inside the cells, the nanoceria particle toxicity could depend on whether the particles are localized in particular cellular organelles, such as the lysosomes which are acidic, or distributed in the cytoplasm which is at neutral pH in normal cells. Since most tumors have an acidic microenvironment, this might switch off nanoceria antioxidant activity, turning on its oxidase activity and consequently sensitizing the tumor towards radiation therapy.
There is always a need for another weapon in the arsenal needed to fight disorders on a cellular level and the present invention provides the needed weaponry.
In the prior art, naked, bare nanoceria particles have been reported wherein the surface charge of the particle is modified. S. Patil et al. in “Protein Adsorption and Cellular Uptake of Cerium Oxide Nanoparticles as a Function of Zeta Potential” Biomaterials, 2007 November, 28 (31): 4600-4607 describes how surface chemistry of biomaterials have an impact on their performance. A. Vincent et al. in “Tuning Hydrated Nanoceria Surfaces: Experimental/Theoretical Investigations of Ion Exchange and Implications in Organic and Inorganic Interactions” Langmuir, 2010, 26 (10), 7188-7198 teaches that surface charge modified hydrated cerium oxide nanoparticles can be synthesized and provide detail of the dynamic ion exchange interactions with the surrounding medium. These surface charge modifications were based on the use of naked, bare, uncoated nanoceria particles.
Other research by C. Wilhelm in “Intracellular Uptake of Anionic Superparamagnetic Nanoparticles as a Function of Their Surface Coating” Biomaterials, 2003 24: 1001-1011 focused on the use of dextran-coated iron oxide nanoparticles to provide negative surface charges.
In co-pending U.S. patent application Ser. No. 12/704,678, with common inventors and common ownership, it is reported that polymer-coated nanoceria has intrinsic oxidase activity at acidic pH values and nanoceria behaves as an oxidant at pH 4. It is also reported that polymer-coated cerium oxide nanoparticles bind to folate expressing cancer cells and can be detected via catalytic oxidation of sensitive colorimetric substrates/dyes. The content of the co-pending U.S. patent application Ser. No. 12/704,678 is incorporated herein by reference.
In co-pending U.S. patent application Ser. No. 11/965,343, with common inventors and common ownership, a method for synthesizing non-toxic, biodegradeable polymer coated nanoceria is disclosed. The polymeric-coatings discussed are at least one of a carbohydrate polymer, a synthetic polyol, a carboxylated polymer and derivatives thereof; the content of the co-pending U.S. patent application Ser. No. 11/965,343 is incorporated herein by reference.
A further co-pending U.S. patent application Ser. No. 12/169,179 with common inventors and common ownership, discloses polymer-coated nanoceria preparations that exhibit no toxicity to normal cells and exhibits pH-dependent antioxidant properties at neutral or physiological pH values and is inactive as an antioxidant at acidic pH values; the pH dependent properties of the polymer-coated nanoceria provides selective cytoprotection. The content of co-pending U.S. patent application Ser. No. 12/169,179 is incorporated herein by reference.